Digitalis glycosides or cardiac glycosides constitute a class of drugs among which are a few of the oldest drugs in current use. Their main utility is in the treatment of cardiac disorders such as cardiac insufficiency and cardiac arrythmias. The term "cardiac glycosides" as used herein includes therapeutically effective naturally occurring digitalis glycosides and similar compounds of different origin including compounds preparable as semisynthetic derivatives of naturally occurring compounds, irrespective of the manner of obtention thereof. Below, the cardiac glycosides are occasionally referred to as "the active ingredient".
Cardiac glycosides are broken down in an acid environment. This effect is seen especially with digoxin, lanatoside C, digitoxin and proscillaridin.
Thus digoxin is hydrolysed very rapidly in a buffer solution of pH 1 leaving only 10% thereof after exposure for 1 hour. Such decomposition also takes place in vivo; thus it is described that 40% of a given dose may be broken down. As some of the products of hydrolysis have a substantially lower biological activity than has the mother substance, this means that the therapeutical response of a given dose of cardiac glycosides may vary between individuals and between moments of administration depending on how long the preparation stays in the stomach and what pH is prevailing at the time of passage.
It is, however, known in the literature that conventional gastric juice resistant preparations of digitalis glycosides such as tablets provided with a conventional enteric coating give an impaired bioavailability of the glycoside. The fact that digitalis glycosides are difficultly soluble in aqueous media make them further difficult to include in pharmaceutical preparations while obtaining a satisfactory bioavailability.
Digitalis glycosides in general have a narrow therapeutical index, i.e. the dose thereof producing toxic or other undesirable side effects is not much greater than the therapeutically effective dose. Several side effects e.g. nausea and arrythmias encountered in treatment with cardiac glycosides are related to a peak in plasma concentration often occurring a few hours after administration of a dose. For these reasons it is strongly desirable to prepare compositions giving a sustained release of the cardiac glycosides. Bio-pharmaceutical studies have, however, shown that hitherto known sustained release preparations have the drawback of giving an impaired bioavailability of the digitalis glycoside.